Brain tumors, particularly brain metastases of systemic cancers such as lung cancer, are a growing problem in the Veterans Administration patient population, and are associated with high morbidity and poor prognosis. Current treatments for brain metastasis such as radiotherapy with or without chemotherapy have only short- term efficacy. Brain metastases show wide heterogeneity in imaging characteristics, immunohistochemical markers, and chemotherapy sensitivity, even among different metastases in the same patient. We postulate that the heterogeneity of the vasculature in individual metastases and peritumoral brain, in terms of both blood volume and vessel permeability, determines and limits the efficacy of chemo-radiotherapy treatments. We propose to evaluate the heterogeneity of brain tumor vasculature using new dynamic magnetic resonance imaging (MRI) techniques, and correlate changes in tumor blood volume and vascular permeability with drug delivery, hypoxia, tumor growth and survival in rat models of brain metastasis. Dynamic susceptibility-weighted MRI with the iron oxide nanoparticle blood pool agent ferumoxytol provides a measure of tumor blood volume while dynamic contrast-enhanced MRI with gadolinium-based contrast agents provides measures of vascular permeability and contrast distribution. Studies will be performed in hematogenous and intracerebral xenograft animal models representative of the four major histopathological subgroups of human lung cancer: LX-1 small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) variants H460 large cell carcinoma, H520 squamous cell carcinoma, and A549 adenocarcinoma. Treatment paradigms will be whole brain radiation therapy with or without temozolomide chemotherapy, and bevacizumab (Avastin), a monoclonal antibody against vascular endothelial growth factor that is effective in human brain tumors. Specific Aim 1 will characterize the heterogeneity of vascular characteristics and drug delivery in untreated xenograft and hematogenous brain metastases. We hypothesize that the tumor vascular permeability will correlate with drug delivery while blood volume will correlate with inflammation, hypoxia, and necrosis in individual metastases. Specific Aim 2 will investigate early and late changes in brain and tumor vasculature following WBRT, and evidence for pseudoprogression after treatment with WBRT plus temozolomide. In Aim 3 we will evaluate the effect of targeting the vasculature in brain metastases using bevacizumab and assess its impact on tumor response versus pseudoresponse. We will assess the effect of combination therapy with bevacizumab, WBRT, and temozolomide on vascular characteristics and survival. For both Aims 2 and 3, we hypothesize that changes in blood volume and vascular permeability will correlate with the growth of individual tumors and survival. The goals of this translational preclinical proposal are to define the effects of targeting tumor vasculature with radiotherapy or bevacizumab on dynamic MRI and to determine the pharmacological and therapeutic effects of these approaches in combination with chemotherapy in rat models of lung cancer brain metastasis. The dynamic MRI techniques are highly effective in determining response to therapy in glioblastoma; the goal of this proposal is to determine the applicability of these approaches in brain metastases and evaluate their potential to demonstrate anti-tumor efficacy. We hypothesize that these approaches will lead to the development of a clinical trial of dynamic MRI and novel therapy that will translate into improved survival of VA patients with lung cancer brain metastases. PUBLIC HEALTH RELEVANCE: Brain metastases of systemic cancers are a growing problem in the VA patient population with no long-term effective treatments. This translational preclinical proposal will define the effects f radiotherapy and anti- angiogenic therapy on brain tumor vasculature using dynamic magnetic resonance imaging in rat models of lung cancer brain metastasis. We will determine whether changes in blood volume and vascular permeability correlate with drug delivery and tumor growth in individual brain metastases, and evaluate their potential to demonstrate the anti-tumor efficacy of combination therapy.